Approaches directed to boosting a host's immune response to address diseases and conditions characterized by a deficiency in immunity or resolvable by a more aggressive immune response have been described. Exemplary diseases or conditions where such approaches may be advantageous include cancer, influenza and human immunodeficiency virus (HIV).
Cancer treatments involving surgery, chemotherapy and radiotherapy are commonly used, but these approaches lack tumor specificity, resulting in adverse side effects and less than satisfactory clinical responses. Accordingly, methods of boosting the immune response to cancer by specifically directing that response to the target cancerous cells without significant, detrimental effects on normal cells would offer distinct advantages over traditional cancer therapy.
There is a consensus that immune surveillance plays a role in the prevention and eradication of tumors, and adaptive immunity mediated by T cells plays a role in this process. See, e.g., Pardoll, Nat. Rev. Immunol. 2002, 2:227-38; Rosenberg, Nature 2001, 411: 380-84; Finn, O J. Nat. Rev. Immunol. 2003, 3:630-41. T cell-mediated immunity also plays a role in various immunotherapeutic approaches that have shown efficacy in preclinical and limited clinical settings. See, e.g., Pardoll, supra; Finn, supra; Antonia et al., Curr. Opin. Immunol 2004, 16:130-6. Tumors are targeted by the immune system because they express tumor associated antigens (TAAs), which are either mutated or over/aberrantly expressed self-proteins, or proteins derived from oncogenic viruses. See, e.g., Finn, supra; Antonio, supra. Under physiological conditions, tumor antigens are picked up by dendritic cells (DC), carried to peripheral lymphoid organs, and presented to naïve T cells under immunogenic conditions allowing for their activation and differentiation into effector cells (Teff). These cells then traffic to tumor sites and generate anti-tumor responses for tumor eradication. See, e.g., Spiotto, et al., Immunity. 2002; 17:737-47; Ochsenbein et al., Nature 2001; 411:1058-64; Yu et al., Nat. Immunol. 2004; 5:141-9.
A productive T cell response requires three distinct signals: Signals 1, 2, and 3. Signal 1 is generated by T cell receptors (TCR) interacting with nominal peptides presented by major histocompatibility complex (MHC) molecules on the surface of professional antigen presenting cells (APCs). Signal 2 is mediated by a series of costimulatory molecules and is critical to a sustained immune response. Signal 3 is transduced via cytokines elaborated by activated lymphocytes and APCs, such as macrophages and DC, and is important to the maintenance of effector immune responses.
Tumors have developed various mechanisms to evade immune surveillance. These mechanisms include: (i) lack of Signal 1, arising from either the inefficient display of MHC/tumor antigen bimolecular complexes on tumor cells, defects in the transduction of this signal, or expression of MHC homologues, MIC, that inhibit natural killer (NK cells) expressing NKG2 inhibitory receptors; (ii) absence of Signal 2 originating from the lack of costimulatory molecules or expression of coinhibitory molecules on tumor cells; (iii) tumor-mediated suppression of immune responses through the secretion of anti-inflammatory molecules, induction of anergy in tumor-reactive T cells, physical elimination of Teff cells via apoptosis, or induction of naturally occurring CD4+CD25+FoxP3+T regulatory (Treg) cells, and (iv) regulation of immunity by the tumor stroma. Accumulating evidence suggests that many of these mechanisms may operate simultaneously in patients with large tumor burdens.
Cancer vaccines which include antigens from the target cancer have attracted particular interest because of the promise of specificity, safety, efficacy and the long-term memory of the immune system that may prevent recurrence of the cancer. Once it was established that the immune system plays an important role in safeguarding individuals against cancer and may be modulated to eradicate existing tumors in animal models, intense efforts were devoted to the development of therapeutic vaccines. See, e.g., Berzofsky et al., J. Clin. Invest 2004, 113:1515-25; Platsoucas et al., Anticancer Res. 2003; 23, 1969-96; Finn, supra. Current vaccine strategies include the use of specific TAAs in conjunction with nonspecific or specific adjuvants, whole tumor cell lysates, tumor cells genetically modified to express costimulatory molecules, cytokines, and/or chemokines, DC pulsed with tumor antigens or transfected with tumor RNA or DNA, and intratumoral injection of a range of vectors encoding various immunostimulatory molecules. The limited efficacy of these approaches may stem from the ability of progressing tumors to control immune responses using one or several immune evasion strategies, or due to immunosuppressive mechanisms, inefficient presentation of TAAs, or lack of potent activation of DC, Teff cells, and NK cells.